The present invention is directed to a process for preparing N-substituted heterocyclic derivatives 4'-[[2-alkyl or alkoxy-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl]methyl][1,1'-biphenyl]-2-car bonitrile and its salts using phase transfer catalysis. These compounds are important intermediates in the synthesis of the final compounds 2-alkyl or alkoxy-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl ]-1,3-diazaspiro[4.4]non-1-en-4-one and its salts which are useful as antagonists of the peptide hormone Angiotensin II.
Angiotensin II is a peptide hormone of the formula H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH.
Angiotensin II is a potent vasopressor and the biologically active product of the renin-angiotensin system. Renin acts on the angiotensinogen of the plasma to produce angiotensin I, which is converted to angiotensin II by the action of the angiotensin I converting enzyme. The final compounds inhibit the action of angiotensin II on its receptors and thus prevents the increase in blood pressure produced by the hormone-receptor interaction. Thus, they are therefore useful in the treatment of hypertension and heart failure.
The preferred intermediate is 4'-[[2-butyl-4-oxo-1,3-diazaspiro [4.4]non-1-en-3-yl]methyl][1,1'-biphenyl]-2-carbonitrile which is useful in the synthesis of the final compound 2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspi ro[4.4]non-1-en-4-one known by the trademark (Irbesartan) and can be easily converted to Irbesartan and its salts according to the process described in U.S. Pat. No. 5,270,317. The compound Irbesartan antagonizes the action of angiotensin II.
A synthetic route for the preparation of N-substituted heterocyclic derivatives has been described in U.S. Pat. No. 5,270,317. The process of U.S. Pat. No. 5,270,317 involves reacting a heterocyclic compound of the formula ##STR1## with a (biphenyl-4-yl)methyl derivative of the formula ##STR2## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and t, z and Hal have the meanings given in said U.S. Pat. No. 5,270,317, in the presence of an inert solvent such as DMF, DMSO or THF, with a basic reagent, for example KOH, a metal alcoholate, a metal hydride, calcium carbonate or triethylamine. The products of the reaction were purified by chromatography.
U.S. Pat. Nos. 5,352,788, and 5,559,233, and WO 91/14679 also describe identical alkylation of the nitrogen atom of the heterocyclic compound with the halo-biphenyl compound using the same inert solvent and the same basic reagents.
Also EP0 475,898 describes the alkylation of the nitrogen atom of the heterocycle of the formula ##STR3## with a compound of the formula ##STR4## wherein X, R.sub.1, Z.sub.1 and Z.sub.6 have the meanings given therein, in the presence of N,N-dimethylformamide and a basic reagent, such as alkalimetalhydrides for example sodium or potassium hydride.
All of the above identified patents describe alkylation in solvents, such as N,N-dimethylformamide or DMSO, etc. in the presence of a basic reagent, for example, a metal hydride or a metal alcoholate etc. The strong bases, such as metal hydride or a metal alcoholate require anhydrous reaction conditions. Since N,N-dimethylformamide is used as a solvent, its removal requires high temperature concentration by distillation, which can result in degradation of the final product. None of these patents describe alkylation using a phase transfer catalysis.
The Journal of Heterocyclic chemistry, 21 477-480, 1984 describes alkylation of hydantoins using a phase-transfer catalysis. The hydantoins are by their electronic nature more acidic than the 2-butyl-1,3-diazaspiro[4.4]nonan-4-one, hydrochloride of the present invention and therefore, there is structural divergence between the two compounds.